구강 편평세포암종에서의 암줄기세포 이론과 최신 지견

김덕훈(Deok-Hun Kim),윤준용(Jun-Yong Yun),이주현(Ju-Hyun Lee),김성민(Soung-Min Kim),명 훈(Hoon Myoung) 대한구강악안면외과학회 2011 대한구강악안면외과학회지 Vol.37 No.2

Cancer stem cells have stem cell-like features, such as the ability for self-renewal and differentiation but show unlimited growth because they have the lost normal regulation of cell growth. Cancer stem cells and normal stem cells have similar features. They show high motility, diversity of progeny, robust proliferative potential, association with blood vessels, immature expression profiles, nestin expression, epidermal growth factor (EGF)-receptor expression, phosphatase and tensin homolog (PTEN) expression, hedgehog pathway activity, telomerase activity, and Wnt pathway activity. On the other hand, with cancer cells, some of these signaling pathways are abnormally modified. In 1875, Cohnheim suggested the concept of cancer stem cells. Recently, evidence for the existence of cancer stem cells was identified. In 1994, the cancer stem cells’specific cell surface marker for leukemia was identified. Since then, other specific cell surface markers for cancer stem cells in solid tumors (e.g. breast and colon cancer) have been identified. In oral cancer, studies on cancer stem cells have been performed mainly with squamous cell carcinomas. Oral cancer specific cell surface markers, which are genes strongly expressed in oral cancer and cancer stem cell specific side populations, have been identified. Cancer stem cells are resistant to radiotherapy and chemotherapy. Therefore, to eliminate malignant tumors efficiently and reduce the recurrence rate, therapy targeting cancer stem cells needs to be performed. Currently, studies targeting the cancer stem cells’specific signaling pathways, telomerase and tumor vasculatures are being done.

유방암 줄기세포 개념 및 제한점

김종빈,안정신,임우성,문병인,Kim, Jong Bin,An, Jeong Shin,Lim, Woosung,Moon, Byung-In 제주대학교 의과학연구소 2018 The Journal of Medicine and Life Science Vol.15 No.2

Cancer, a leading mortality disease following cardiovascular disease worldwide, has high incidence as one out of every four adults in Korea. It was known to be caused by several reasons including somatic mutation, activation of oncogene and chromosome aneuploidy. Cancer cells show a faster growth rate and have metastatic and heterogeneous cell populations compared to normal cells. Cancer stem cells, the most invested field in cancer biology, is a theory to explain heterogeneous cell populations of cancer cells among several characteristics of cancer cells, which is providing the theoretical background for incidence of cancer and treatment failure by drug resistance. Cancer stem cells initially explain heterogeneous cell populations of cancer cells based on the same markers of normal stem cells in cancer, in which only cancer stem cells showed heterogeneity of cancer cells and tumor initiating ability of leukemia. Based on these results, cancer stem cells were reported in various solid cancers such as breast cancer, liver cancer, and lung cancer. Breast cancer stem cells were first reported in solid cancer which had tumor initiating ability and further identified as anti-cancer drug resistance. There were several identification methods in breast cancer stem cells such as specific surface markers and culture methods. The discovery of cancer stem cells not only explains heterogeneity of cancer cells, but it also provides theoretical background for targeting cancer stem cells to complete elimination of cancer cells. Many institutes have been developing new anticancer drugs targeting cancer stem cells, but there have not been noticeable results yet. Many researchers also reported a necessity for improvement of current concepts and methods of research on cancer stem cells. Herein, we discuss the limitations and the perspectives of breast cancer stem cells based on the current concept and history.

Comparison of CD133 and ABCG2 Expression in Cancer Stem Cells

JaYoungKim,EunKyungAhn,SeunJaPark,YoungHoKim,SunHeeLeem,JeonghoonHeo 한국조직공학·재생의학회 2011 조직공학과 재생의학 Vol.8 No.5

Cancer stem cells in various tumors have been isolated by antigenic markers on cell surface or functional markers for cancer stem cells. The purpose of this study is explore if the expression of CD133, known as surface marker for common cancer stem cells, is related to the expression of ABCG2, known as the functional marker for stem cells in various cancer cell lines. We determined the expression of CD133 and ABCG2 in the established human gastric cancer cell line (SNU216), hepatoblastoma cell line (HepG2), colon cancer cell line (SNU1040), and brain tumor cell line (A172). SNU 216 and SNU 1040 cells showed a higher level of CD133 expression, whereas HepG2 and A172 cells expressed almost undetectable level of CD133. However the expression level of ABCG2 was higher in HepG2 and A172 cells than in SNU 216 and SNU 1040 cells. 5-FU treatment increased both of the CD133 and ABCG2 expression in SNU216 and SNU1040 cells, but not in HepG2 and A172. The expression of ABCG2 in CD133 positive population of SNU1040 and A172 cells was higher than in CD133 negative population. This study showed there is a relationship between CD133 and ABCG2 expression in some cancer cell lines but not in all. CD133 positive cells expressing ABCG2 in a high level may be more resistant to anti-cancer drug, which suggest that CD133 might be a useful marker to isolate cancer stem cells having a resistance to anti-cancer-drug.

Efficient Cell Fusion Model of Stem Cells and Cancer Cells

( Eun Kyung Ahn ),( Young Ho Kim ),( Ja Young Kim ),( Sun Hee Leem ),( Jeong Hoon Heo ) 한국조직공학·재생의학회 2009 조직공학과 재생의학 Vol.6 No.14

Cancer stem cells represent a minor population of a tumor and have the property of self-renewal. Although there are many reports demonstrating the presence of cancer stem cells in various tumors, the origin of cancer stem cells is still unknown. The purpose of this study is to develop an efficient system for cell fusion study and to demonstrate the spontaneous fusion of normal stem cells with cancer cells in vitro or in vivo. To detect and select the fused cells efficiently, mouse hepatoma cells transfected with beta-actin promoter-cherry fluorescent protein gene and puromycin resistant protein gene (BC-Hepa cells) were fused with mouse embryonic stem cells with albumin promoter-green fluorescence protein reporter gene and neomycin resistant gene (AG-ES cells) by forming embryoid body (EB) for in vitro fusion or by injecting into nude mice for in vivo fusion. The fusion of AG-ES cells with BC-Hepa cells occurred efficiently in vivo rather than in vitro. The fused cells expressed ALB, GFP, CFP, PECAM, and HNF4 but did not express OCT4. The fused cells induced the formation of tumor comparable to the tumor formed by BC-Hepa cells. This study demonstrated that cancer cells can fuse with stem cells in vivo, which suggest a possibility that the fusion of cancer cells with stem cells can generate cancer stem cells.

Functionalizing Liposomes with Dual Aptamers for Targeting of Breast Cancer Cells and Cancer Stem Cells

Hee-Bin Park,Ji-Eun You,Pyung-Hwan Kim,Keun-Sik Kim 대한의생명과학회 2021 Biomedical Science Letters Vol.27 No.1

Cancer stem cells, which are known to drive tumor formation and maintenance, are a major obstacle in the effective treatment of various types of cancer. Trans-membrane glycoprotein mucin 1 antigen and cell surface glycogen CD44 antigen are well-known surface markers of breast cancer cells and breast cancer stem cells, respectively. To effectively treat cancer cells and cancer stem cells, we developed a new drug-encapsulating liposome conjugated with dual-DNA aptamers specific to the surface markers of breast cancer cells and their cancer stem cells. These two aptamer (Apt)-targeted liposomes, which were prepared to encapsulate doxorubicin (Dox), were named "Dual-Apt-Dox". Dual-Apt-Dox is significantly more cytotoxic to both cancer stem cells and cancer cells compared to liposomes lacking the aptamers. Furthermore, we demonstrated the inhibitory efficacy of Dual-Apt-Dox against the experimental lung metastasis of breast cancer stem cells and cancer cells in athymic nude mice. We also showed the potent antitumor effects of dualaptamer-conjugated liposome systems by targeting cancer cells as well as cancer stem cells. Thus, our data indicate that dual-aptamer-conjugated liposome systems can prove to be effective drug delivery vehicles for breast cancer therapy.

Correlation analysis of cancer stem cell marker CD133 and human endogenous retrovirus (HERV)-K env in SKOV3 ovarian cancer cells

Kim Do-Ye,Kim Heungyeol,Ko Eun-Ji,Koh Suk Bong,Kim Hongbae,Lee Ji Young,Lee Chul Min,Eo Wan Kyu,Kim Ki Hyung,Cha Hee-Jae 한국유전학회 2024 Genes & Genomics Vol.46 No.4

Background Human endogenous retrovirus (HERV)-K is a type of retrovirus that is present in the human genome, and its expression is usually silenced in healthy tissues. The precise mechanism by which HERV-K env influences cancer stemness is not fully understood, but it has been suggested that HERV-K env may activate various signaling pathways that promote stemness traits in cancer cells. Objective To establish the connection between HERV-K env expression and cancer stemness in ovarian cancer cells, we carried out correlation analyses between HERV-K env and the cancer stem cell (CSC) marker known as the cluster of differentiation 133 (CD133) gene in SKOV3 ovarian cancer cells. Method To perform correlation analysis between HERV-K env and CSCs, ovarian cancer cells were cultured in a medium designed for cancer stem cell induction. The expression of HERV-K env and CD133 genes was verified using quantitative real-time polymerase chain reaction (RT-qPCR) and Western blot analyses. Additionally, the expression of stemness-related markers, such as OCT-4 and Nanog, was also confirmed using RT-qPCR. Results In the stem cell induction medium, the number of tumorsphere-type SKOV3 cells increased, and the expression of CD133 and HERV-K env genes was up-regulated. Additionally, other stemness-related markers like OCT-4 and Nanog also exhibited increased expression when cultured in the cancer stem cell induction medium. However, when HERV-K env knockout (KO) SKOV3 cells were cultured in the same cancer stem cell induction medium, there was a significant decrease in the number of tumorsphere-type cells compared to mock SKOV3 cells subjected to the same conditions. Furthermore, the expression of CD133, Nanog, and OCT-4 did not show a significant increase in HERV-K env KO SKOV3 cells compared to mock SKOV3 cells cultured in the same cancer stem cell induction medium. Conclusion These findings indicate that the expression of HERV-K env increased in SKOV3 cells when cultured in cancer stem cell induction media, and cancer stem cell induction was inhibited by KO of HERV-K env in SKOV3 cells. These results suggest a strong association between HERV-K env and stemness in SKOV3 ovarian cancer cells. Background Human endogenous retrovirus (HERV)-K is a type of retrovirus that is present in the human genome, and its expression is usually silenced in healthy tissues. The precise mechanism by which HERV-K env influences cancer stemness is not fully understood, but it has been suggested that HERV-K env may activate various signaling pathways that promote stemness traits in cancer cells. Objective To establish the connection between HERV-K env expression and cancer stemness in ovarian cancer cells, we carried out correlation analyses between HERV-K env and the cancer stem cell (CSC) marker known as the cluster of differentiation 133 (CD133) gene in SKOV3 ovarian cancer cells. Method To perform correlation analysis between HERV-K env and CSCs, ovarian cancer cells were cultured in a medium designed for cancer stem cell induction. The expression of HERV-K env and CD133 genes was verified using quantitative real-time polymerase chain reaction (RT-qPCR) and Western blot analyses. Additionally, the expression of stemness-related markers, such as OCT-4 and Nanog, was also confirmed using RT-qPCR. Results In the stem cell induction medium, the number of tumorsphere-type SKOV3 cells increased, and the expression of CD133 and HERV-K env genes was up-regulated. Additionally, other stemness-related markers like OCT-4 and Nanog also exhibited increased expression when cultured in the cancer stem cell induction medium. However, when HERV-K env knockout (KO) SKOV3 cells were cultured in the same cancer stem cell induction medium, there was a significant decrease in the number of tumorsphere-type cells compared to mock SKOV3 cells subjected to the same conditions. Furthermore, the expression of CD133, Nanog, and OCT-4 did not show a significant increase in HERV-K env KO SKOV3 cells compared to mock SKOV3 cells cultured in the same cancer stem cell induction medium. Conclusion These findings indicate that the expression of HERV-K env increased in SKOV3 cells when cultured in cancer stem cell induction media, and cancer stem cell induction was inhibited by KO of HERV-K env in SKOV3 cells. These results suggest a strong association between HERV-K env and stemness in SKOV3 ovarian cancer cells.

만성 Helicobacter pylori 감염에 의한 위암발생에서 위줄기세포의 역할

박무인,허정훈 대한상부위장관ㆍ헬리코박터학회 2015 Korean Journal of Helicobacter Upper Gastrointesti Vol.15 No.3

Gastric cancer is a disease with the second cancer-related mortality in the world. Helicobacter pylori infection that is one of major causes of gastric carcinogenesis induces a chronic inflammation in stomach. The epithelial-mesenchymal transition and/or the accumulation of genetic mutation occur during regenerating the injured gastric epithelial cells due to chronic inflammation by the infection of H. pylori. Normal gastric cells can be transformed into cancer stem cells by the epithelial-mesenchymal transition and/or the accumulation of genetic mutation that initiate the development of gastric cancer. Gastric epithelial cells, bone marrow-derived cells and gastric stem cells in gastric tissue might be the source of gastric cancer stem cells as the target cells that might be susceptible for epithelial-mesenchymal transition and/or the accumulation of genetic mutation. Normal stem cells in gastric tissue regenerating the injured gastric tissue also have the potential to be cancer stem cells known as the origin of cancer development when their ability for regulating differentiation and/or proliferation of normal stem cells is damaged by epithelial-mesenchymal transition and/or the accumulation of genetic mutation. Therefore if the mechanism regulating the transformation of normal stem cells to cancer stem cells is discovered, it might suggest the fundamental therapeutic strategy for preventing the development of gastric cancer by the chronic infection of H. pylori.

Liver Cancer Stem Cell Induction from Induced Pluripotent Stem Cells

( Said M Afify ),( Ghmkin Hassan ),( Hend M Nawara ),( Hager M Mansour ),( Amira Osman ),( Sadia Monzur ),( Hagar Ali Abu Quora ),( Maram H Zahra ),( Akimasa Seno ),( Yoshiaki Iwasaki ),( Masaharu Sen 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: Liver cancer stem cells represent a small fraction of cells in liver cancer tissues so that studying these cells is very hard. Generation of liver cancer stem cells considered as one of the most important issue in cancer biology research. For this reason, we tried to generate liver cancer stem cells from induced pluripotent stem (iPSCs). Methods: First of all, CM was collected from confluent culture of Huh7 cells. Then, mouse iPSCs cells without MEF feeder cells were cultured in the presence of 50% CM for 4 weeks. The medium was changed every day with fresh medium containing 50% of CM. Mouse iPSCs cultured is the complete medium with LIF were used as a control. The survived cells (5x105 cells) were suspended in HBSS and injected into the liver of BALB/ c nude mice. After 25 days malignant tumor was formed in the liver while benign teratoma was formed by the injection of iPSCs. Tumors were then excised and partly fixed in 10% neutral formalin buffer solution for HE staining and immunohistochemical analysis. The rest of tumors were subjected to rt-qPCR anaylsis and primary culture. Results: Immunohistochemical analysis with liver cancer associated markers and cancer stem cell marker showed that malignant liver tumor was developed. These results indicate that the primary cells from the malignant tumor are rich in CSCs. Conclusions: This model will be very important and useful to assess the significant molecular mechanisms necessary to maintain liver cancer stem cells, which will help in defat liver cancer.

Deubiquitylating enzymes as cancer stem cell therapeutics

Haq, Saba,Suresh, Bharathi,Ramakrishna, Suresh Elsevier 2018 Biochimica et biophysica acta, Reviews on cancer Vol.1869 No.1

<P><B>Abstract</B></P> <P>The focus of basic and applied research on core stem cell transcription factors has paved the way to initial delineation of their characteristics, their regulatory mechanisms, and the applicability of their regulatory proteins for protein-induced pluripotent stem cells (protein-IPSC) generation and in further clinical settings. Striking parallels have been observed between cancer stem cells (CSCs) and stem cells. For the maintenance of stem cells and CSC pluripotency and differentiation, post translational modifications (i.e., ubiquitylation and deubiquitylation) are tightly regulated, as these modifications result in a variety of stem cell fates. The identification of deubiquitylating enzymes (DUBs) involved in the regulation of core stem cell transcription factors and CSC-related proteins might contribute to providing novel insights into the implications of DUB regulatory mechanisms for governing cellular reprogramming and carcinogenesis. Moreover, we propose the novel possibility of applying DUBs coupled with core transcription factors to improve protein-iPSC generation efficiency. Additionally, this review article further illustrates the potential of applying DUB inhibitors as a novel therapeutic intervention for targeting CSCs. Thus, defining DUBs as core pharmacological targets implies that future endeavors to develop their inhibitors may revolutionize our ability to regulate stem cell maintenance and differentiation, somatic cell reprogramming, and cancer stem cells.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Addressing the applications of deubiquitylating enzymes (DUBs) in applied stem cell research and cancer stem cells therapy </LI> <LI> Efficient protein-induced pluripotent stem cells generation by DUBs-mediated extension of half-life of Yamanaka factors </LI> <LI> Discussing the importance of cancer stem cells associated DUBs and developing inhibitors for CSCs-based therapy </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Oncogenic Challenges in Stem Cells and the Link to Cancer Initiation

이지선,차혁진,배갑용,이미옥 대한약학회 2012 Archives of Pharmacal Research Vol.35 No.2

Adult stem cells, which are characterized by self-renewal and multi-potency, are classified as specialized cell types, responsible for the regeneration of damaged tissues. There is growing evidence that senescence of stem cells (or stem cell aging) is closely associated with a variety of aging-related diseases such as tissue atrophy, degenerative diseases and onset of cancers. Alterations in the systemic environment during aging may trigger stress signaling in stem cells and reduce stem cell characteristics, resulting in loss of differentiation potential and defective self-renewal (referred to as mal-differentiation). Thus, it has been suggested that aging-related disorders such as retarded regeneration of damaged tissue and onset of cancer may result from the mal-differentiation of stem cells. In particular, many types of cancers such as leukemia, intestinal cancer, skin cancer and sarcoma have been shown to originate from adult stem cells after a variety of oncogenic challenges. This review summarizes recent studies on cancers originating from stem cells, demonstrating possible molecular mechanisms that govern the susceptibility of stem cells to oncogenic challenges.